3- Aminopiperidines

A-methyl-4-aminopiperidine-3-carboxylic acid, m.p. 241° dec.) and A-methyltetrahydronicotinamide, m.p. 148° (arecaidineamide). ... 

The benzoic acid moiety common to many of the benzamides is prepared in straightforward manner from the methyl ether of p-aminosalicylic acid 141. Acylation on nitrogen (142) followed by chlorination gives intermediate 143 benzoic acid 144 is then obtained by removal of the acetyl group. Condensation of this acid with an aminopiperidine could be achieved by means of the mixed anhydride (prepared by reaction with ethyl chlonoformate), which affords clebopride (145). Reaction with 3-aminoquinuclidine (146) of the intermediate prepared from acid 144 with carbonyldiimidazole affords zacopride (147) [36]. 

The synthesis of a benzamide with a somewhat more complex side chain starts by condensation of acid 144 with racemic cis-aminopiperidine 152. Removal of the benzyl group of 153 by hydrogenolysis gives the secondary amine 154. Alkylation on nitrogen with the halide 155 gives finally the dopamine antagonist, cisapride (156) [38,39]. 

This ring system could be prepared by thionation of benzil monohydrazone 172 with Lawesson s reagent (LR) followed by cyclization. The reaction gives 2,3-diphenyl-7,8,9,9a-tetrahydro-27/,677-pyrido[2,TA][l,3,4]thiadiazine 173 in a diastereoselective way, with the hydrogens at 2- and 9a-position in trans orientation. Benzil monohydrazone 172 was obtained by condensation of benzil 170 with 1 equiv of iV-aminopiperidine 171 (Scheme 23) <1998TA1531>. 

A number of patent applications that describe small molecule inhibitors of SCD-1 have recently published. For example, a series of patent applications describe related piperazine-based inhibitors of SCD-1 (exemplified by 19) [85]. Piperazine replacements, such as piperidine, 4-aminopiperidine, and 3-amino-azetidine are tolerated, as are thiadiazole and pyridine surrogates of the 1,2-diazine [86-90]. 

NOC might be generated by aerial oxidation of the hydrazines. Experimental studies on oxidation of 1,1-dimethylhydrazine which is not a mutagen and Af-aminopiperidine which is a mutagen indicated that the oxides of both hydrazide samples were mutagenic103. 

A four-step solution-phase synthesis of 4-aminopiperidines containing four sites of diversity is shown in Scheme 12.23 Polymer-assisted steps involved... 

Desai, M. C. and Rosen, T. J. (Pfizer, Inc., U.S.A.) Preparation of 3-aminopiperidine derivatives and related nitrogen-containing heterocycles, W09301170. 

Reaction of l-aminopiperidine-2-carboxylates 27 and (benzo[l,2,4]thiadia-zin-3-yl)acetic acid 28 in the presence of DCC, followed by the treatment with NaOEt afforded pyrido[l,2-fc]pyridazin-2-ones 3 (08BML5002, 08WOP2008 /073987). 

Enantiomers of 3-[(4-aminopiperidin-l-yl)methyl]-5-oxo-2,3-dihy-dro-5H-pyrido[l,2,3-cfe][l,4]benzoxazine-10-carbonitril and 10-meth-oxy-3-( 4-[(3-oxo-3,4-dihydro-2H-pyrido[3,2-fr][l,4]oxazin-6-yl)methyla-mino]piperid-l-yl methyl)-2,3-dihydro-5H-pyrido[l,2,3-de][l,4]benzox-azin-5-one were separated by chiral HPLC (08WOP2008/120003). 

Another successful approach to replacing the benzhydryl stereocenter has been to synthesize and evaluate diarylamines with pendant basic amines. A simple transposition of the nitrogen and carbon atoms of the benzhydryl-piperazine leads to diarylaminopiperidine delta opioid agonists, as Carroll and coworkers at the Research Triangle Institute (RTI) demonstrated [30]. Scientists at AstraZeneca [31] and the R.W. Johnson Research Institute [32] have also disclosed delta opioid agonists possessing the carbon-nitrogen transposition. Boyd and coworkers at R.W. Johnson were the first to report on compounds where the aminopiperidine was further constrained as an aminotropane. Compound 47 has a K = 0.4 nM at the delta opioid receptor, with 14000-fold selectivity versus the mu opioid receptor (Fig. 8). 

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